No abstract

The synthesis, structure-activity relationship (SAR) studies, and antidiabetic characterization of 1,2-dihydro-4-[[4-(methylthio)phenyl]methyl]-5-(trifluoromethyl)-3H- pyrazol-3-one (as the hydroxy tautomer; WAY-123783, 4) are described. Substitution of 4-methylthio, methylsulfinyl, or ethyl to a benzyl group at C4, in combination with trifluoromethyl at C5 of pyrazol-3-one, generated potent antihyperglycemic agents in obese, diabetic db/db mice (16-30% reduction in plasma glucose at 2 mg/kg). The antihyperglycemic effect was associated with a robust glucosuria (> 8 g/dL) observed in nondiabetic mice. Chemical trapping of four of the seven possible tautomeric forms of the heterocycle by mono- and dialkylation at the acidic hydrogens provided several additional potent analogs (39-43% reduction at 5 mg/kg) of the lead 4 as well as a dialkylated pair of regioisomers that showed separation of the associated glucosuric effect produced by all of the active analogs in normal mice. Further pharmacological characterization of the lead WAY-123783 (ED50 = 9.85 mg/kg, po in db/db mice), in oral and subcutaneous glucose tolerance tests, indicated that unlike the renal and intestinal glucose absorption inhibitor phlorizin, pyrazolone 4 does not effectively block intestinal glucose absorption. SAR and additional pharmacological data reported herein suggest that WAY-123783 represents a new class of potent antihyperglycemic agents which correct hyperglycemia by selective inhibition of renal tubular glucose reabsorption.

1H NMR based on the CRAMPS technique has been used to identify and monitor the protons of surface Al−OH groups and “physisorbed” water associated with a high-surface-area (230 m2/g) pseudo-boehmite material following dehydration in the 110−1100 °C temperature range. Three distinguishable 1H CRAMPS peaks were identified:  a broad peak at 4.0 ± 0.2 ppm attributed to the protons of “physisorbed” water and two peaks at 8.2 ± 0.3 and 2.3 ± 0.2 ppm associated with the protons of structural Al−OH groups. The 1H CRAMPS results are interpreted in relationship to two important regions of the experimental dehydration weight-loss profile for this material, a lower temperature region (110−300 °C), in which desorption of “physisorbed” water occurs, and an intermediate temperature region (350−550 °C), where condensation of adjacent Al−OH groups occurs. The combination of heating between 110 and 300 °C and room temperature evacuation were found to eliminate the “physisorbed” water peak, permitting the observation of the two resonances associated with the structural Al−OH sites. Dipolar dephasing experiments indicate that the 8.2 ppm peak is associated with highly coupled, “clustered” Al2OH groups, while the 3.0 ppm resonance is associated with terminal, “isolated” AlOH groups. 1H CRAMPS evidence shows that upon heat treatment the Al2OH groups condense at lower temperatures (350 °C) than the AlOH groups (550 °C). Three mechanisms are proposed for the condensation of the proton-containing surface Al−OH groups that occur in this material, based on crystalline boehmite as a structural model. In addition to 1H CRAMPS studies, 27Al MAS NMR spectra at 14 T of samples dehydrated from 100 to 1100 °C provide structural information about the aluminums in the high-surface-area pseudo-boehmite. This material dehydrates by condensation of both Al2OH and AlOH groups to form distorted, hydrogen-bearing 4-, 5-, and 6-coordinate aluminum-containing intermediates in the 350−500 °C range. At 1100 °C, this hydrogen-bearing γ- or δ-alumina material is converted to a material consisting of primarily α-Al2O3.

A class of melt‐quenched silicate glasses, containing calcium, phosphorus and alkali metals, and having the ability to promote bone regeneration and to fuse to living bone, creating strong implants with less danger of interfacial instability than previous materials, is produced commercially as Bioglass® and sold under the brand names of PerioGlas®, NovaBone® and NovaBone‐C/M®. We have collected the first high energy X‐ray and neutron diffraction data, on this important material in the hope of providing more direct experimental insight into the glass structure. Similarly, the first solid state MAS (magic angle spinning) 29Si, 31P, and 23Na NMR data on the material is presented. The diffraction data has been modeled using the reverse Monte Carlo (RMC) method to allow the identification of the atomic‐scale structural features present; the solid state NMR data is used explicitly within the model‐building process as a constraint on the connectivity of the network. The 29Si NMR suggests that the host silica network primarily consists of chains and rings of Q2 SiO4 tetrahedra, with some degree of cross linking as represented by the presence of Q3 units. The diffraction‐based RMC model suggests a Na–O distance of 2.35 Å and a corresponding coordination of ∼ 6; the coordination number is supported by the 23Na NMR data presented here which reveals that the likely sodium environment is six‐coordinate in pseudo‐octahedral arrangement. The RMC model provides evidence for the non‐uniform distribution of Ca, which is in line with previous molecular dynamics simulation results, and the data is also suggestive of CaO as the associated structural motif within the high calcium content regions of the glass.